Stem cell fate in cancer growth, progression and therapy resistance

Abstract

Although we have come a long way in our understanding of the signals that drive cancer growth, and how these signals can be targeted, effective control of this disease remains a key scientific and medical challenge. The therapy resistance and relapse that are commonly seen are driven in large part by the inherent heterogeneity within cancers that allows drugs to effectively eliminate some, but not all, malignant cells. Here, we focus on the fundamental drivers of this heterogeneity by examining emerging evidence that shows that these traits are often controlled by the disruption of normal cell fate and aberrant adoption of stem cell signals. We discuss how undifferentiated cells are preferentially primed for transformation and often serve as the cell of origin for cancers. We also consider evidence showing that activation of stem cell programmes in cancers can lead to progression, therapy resistance and metastatic growth and that targeting these attributes may enable better control over a difficult disease.

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Fig. 1: Impact of the cell of origin on cancer development.
Fig. 2: Epigenetic regulation of the stem cell state in cancer.
Fig. 3: Asymmetric division in cancer.
Fig. 4: Metastasis and cancer stem cells.
Fig. 5: Therapy resistance in cancer stem cells.

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Acknowledgements

The authors thank M. Kritzik for her help with the preparation of the manuscript. N.K.L. received support from US National Institutes of Health (NIH) grant T32 GM00752 and NIH National Research Service Individual Award F31 CA206416. A.G.B. received support from NIH grant R01 DK099335-S1 and NIH grant T32 CA121938. T.R. was supported by NIH grant R35 CA197699 and a Stand Up To Cancer–Cancer Research UK–Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16).

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N.K.L., A.G.B. and T.R. researched data for the article, wrote the article and reviewed or edited the manuscript before submission. N.K.L. and T.R. also made substantial contributions to the discussion of content.

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Correspondence to Tannishtha Reya.

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Glossary

Stem cell

A cell that has the ability to perpetuate itself through self-renewal and to generate differentiated cells. Stem cells are relatively rare among other cell types and can be more quiescent and resistant to toxins and chemicals as well as display enhanced DNA repair.

Stem cell signals

Also called stem cell programmes, these are signals or gene expression programmes that are often associated with the undifferentiated state in embryonic and adult stem cells. Many stem cell programmes or signalling pathways are reactivated in oncogenesis.

Cancer stem cells

(CSCs). Cells with enriched functional capacity to drive tumour growth and recreate its heterogeneity. CSCs generally share many of the defining characteristics of normal stem cells, including increased drug resistance and DNA repair.

Asymmetric division

A method of cellular diversification via differential segregation and inheritance of fate determinants leading to differently fated daughter cells. Controlled asymmetric division can be critically important during development but can become dysregulated during tumour initiation and progression.

Symmetric division

A method of cell division in which fate determinants are equivalently segregated. The resulting pair of daughter cells can either be undifferentiated (symmetric renewal) or differentiated daughter cells (symmetric commitment).

Tumour heterogeneity

Here, refers to the presence of functionally distinct malignant cells within a tumour. Heterogeneity can be driven by different genomic, transcriptomic or epigenetic landscapes.

Side population

A small population of cells detected via flow cytometry that has increased dye efflux, a property that is associated with an increased expression of drug transporters. Functionally, the side population is enriched for cells with the ability to self-renew and differentiate. As these are key features of stem cells, the side population has traditionally been found to be enriched in stem cells and cancer stem cells.

Nutlin-3a

A drug that inhibits the interaction of E3 ubiquitin-protein ligase MDM2 and p53 and is most effective on cells with wild-type p53 expression. Once released, wild-type p53 can induce cell cycle arrest and apoptosis.

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Lytle, N.K., Barber, A. & Reya, T. Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer 18, 669–680 (2018). https://doi.org/10.1038/s41568-018-0056-x

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